Effectors of presynaptic cAMP dependent potentiation at mossy fiber synapses_Diversity Supplement

苔藓纤维突触突触前 cAMP 依赖性增强效应器_Diversity Supplement

• 批准号: 10810245
• 负责人: Anis Contractor
• 金额: $ 7.77万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10810245
• 关键词: Affect; Affinity; Axon; Behavior; Brain; Brain region; Characteristics; Chemosensitization; Cognition; Complex; Cyclic AMP; Disease; Frequencies; Hippocampus; Interneurons; Mediating; Membrane; Molecular; Neurodevelopmental Disorder; Pattern; Play; Presynaptic Terminals; Probability; Process; Property; Protein Binding Domain; Pyramidal Cells; Role; Stratum Lucidum; Synapses; Synaptic Vesicles; Synaptic plasticity; cognitive process; complement C2a; dentate gyrus; experimental study; granule cell; mossy fiber; neural circuit; neural patterning; postsynaptic; presynaptic; sensor; synaptotagmin; synaptotagmin VII

Abstract: Short term synaptic plasticity is a dynamic process that provides moment to moment fluctuations in synaptic strength, but connecting these dynamic changes to complex cognitive processes has been difficult. The mossy fiber (MF) to CA3 synapse in the hippocampus provides a unique opportunity to assess a highly dynamic synapse in a microcircuit important for pattern separation tasks. This microcircuit is formed by the MF axons of dentate gyrus (DG) granule cells (GC) forming en passant synapses with excitatory CA3 pyramidal cells (PYRs), and local circuit inhibitory Stratum lucidum interneurons (SLINs). Critically, these two synaptic connections are central to the role of the MF as a high pass filter of information from the DG to CA3. The low release probability connections onto PYRs show significant facilitation when activated at modest frequencies. In contrast, the high release probability synapses at SLINs depress during elevated bouts of activity, reducing feedforward inhibition. These compartmentalized presynaptic properties of the MF allow the synapses to function as conditional detonators, filtering information from the DG to CA3 and allowing GC bursting activity to produce suprathreshold post synaptic summation on the CA3 network. Yet the mechanisms that control this fundamental property of this important hippocampal microcircuit are not fully known. Presynaptic Ca2+ sensors are known to mediate a major component of synaptic facilitation. Specifically, the high affinity Ca2+ sensor Synaptotagmin 7 (Syt7) is critical for facilitation at synapses in multiple brain regions, including the MF to CA3 PYR synapse. Yet there remain many outstanding questions about how this specialized sensor controls release. Crucially, it remains unknown what roles Syt7 plays in facilitation and other steps in the synaptic vesicle (SV) cycle. Here, I will address whether the subcellular localization and activity of Syt7 is compartmentalized in MF synaptic terminals, and how this affects the CA3 microcircuit. I will determine whether Syt7 is primarily associated with MF SVs, like other synaptotagmins that control release, or whether it is localized to non-vesicular membranes, where it plays a specialized role in other aspects of the SV cycle such as pool replenishment. Finally, I will examine the unique properties of Syt7 that are bestowed by the C2A Ca2+ binding domains of the protein. Together these experiments will establish how the molecular identity and functional characteristics of Ca2+ sensors define the network properties of the CA3 microcircuit.

抽象的： 短期突触可塑性是一个动态过程，可以在突触中提供力矩波动 力量，但是将这些动态变化与复杂的认知过程联系起来很困难。苔藓 海马中的纤维（MF）至CA3突触提供了一个独特的机会来评估高度动态的 微电路中的突触对于模式分离任务很重要。该微电路由MF轴突形成 齿状回（DG）颗粒细胞（GC）与兴奋性CA3锥体细胞形成传球突触 （PYRS）和局部回路抑制性露西神经元（SLIN）。至关重要的是这两个突触 连接是MF作为从DG到CA3的高通滤波器的作用的核心。低 当以适中的频率激活时，释放概率连接显示出明显的促进。 相比之下，在活动升高期间，较高的释放概率突触下降，减少 进食抑制。这些MF的这些分隔的突触前特性允许突触 充当条件雷管，将信息从DG到CA3过滤，并允许GC爆发活动 在CA3网络上生产突触总和。然而，控制这一点的机制 这种重要的海马微电路的基本特性尚不完全清楚。 已知突触前Ca2+传感器可以介导突触促进的主要组成部分。具体来说， 高亲和力Ca2+传感器突触7（SYT7）对于多个大脑区域突触的促进至关重要， 包括MF到CA3 PYR突触。然而，关于如何这样做仍然有许多杰出的问题 专用传感器控件释放。至关重要的是，SYT7在促进和 突触囊泡（SV）周期的其他步骤。在这里，我将解决亚细胞本地化和 SYT7的活性在MF突触终端中被划分，以及这如何影响CA3微电路。我会 确定SYT7是否主要与MF SV相关，例如控制释放的其他突触量 它是否本地化为非二膜膜，在SV的其他方面起着专门的作用 循环，例如泳池补充。最后，我将研究SYT7的独特属性 蛋白质的C2a Ca2+结合结构域。这些实验将共同确定分子身份如何 CA2+传感器的功能特性定义了CA3微电路的网络性能。